This is a competitive renewal application from an inter-institutional group of investigators with long-standing interest in Angelman syndrome (AS), Rett syndrome (RTT), and Prader-Willi syndrome (PWS) to continue a Rare Diseases Clinical Research Center (RDCRC) within the Rare Diseases Clinical Research Network (RDCRN). The Center will focus on these three disorders based on the expectation that the near-term potential for meaningful therapy is strong. The specific aims for RTT will be 1) to establish phenotype/genotype correlations over a broad spectrum of Rett phenotypes, 2) to perform longitudinal studies on an extensive population of individuals with Rett, and 3) to extend the survival study on a broad spectrum of Rett individuals. Recent results from studies in animal models provide a basis for clinical trials in the next 5 years. In addition, evidence emerging from the proposed pilot study on sleep dysfunction in the three disorders should provide the basis for a clinical trial on sleep in RTT. The RTT component sites include UAB, Children's Hospital Boston, Greenwood Genetic Center, and Baylor College of Medicine. GCRCs will be utlized in Birmingham, Boston, and Houston. The travel clinics in Oakland, Chicago, New Brunswick, and Miami will continue to provide geographic diversity for study participants. The Center is expected to function synergistically with the Intellectual and Developmental Disability Center-IDDRC (formerly the MRRC) at UAB, Children's Hospital Boston, and Baylor. An extensive training program is proposed for stimulating the entry of new investigators into clinical research on rare diseases (funded by IRSF and PWSA). The RTT sites will have active affiliation with the International Rett Syndrome Foundation (IRSF). A website for this RDCRC is available at www.circ.uab.edu. This site will be amplified to include a wide range of information on all three disorders.